Para-halogenphenyl-pybidyl



Patented Feb. 12, 1952 PARA-HALOGENPHENYL-PYRIDYL- ALKANONES Karl Hoffmann, Binningen, and Eugen Tagmann,

Basel, Switzerland, assignors to .Ciba Pharmaceutical Products, 1110., Summit, N. J.

No Drawing. Application August 21, 1950, Serial. No. 180,702. In Switzerland March 2, 1950 This invention relates to the manufacture of para-halgenphenyl-pyridyl-alkanones of ithe formula and their salts. In the above formula, R indicates a bivalent aliphatic hydrocarbon radical with two to six carbon atoms, such for example, as an ethylene or propylene group, R1 indicates lower alkyl I I lower alkyl especially a dimethylamino group,

cycloalkyl lower alkyl or N=D, D representing the atoms necessary to complete an alkyleneimino group, for example, a pyrrolidine or piperidine ring, R2 indicates a lower aliphatic, straight .or branched hydrocarbon radical, such as a methyl, ethyl or propyl group; and Hal is a halogen atom, especially chlorine. a

The new compounds exhibit interesting pharmacological properties. Thus they have a lasting histaminolytic effect. .Of particular value is the 1 dimethyl amino 3 pyridyl-(Z') -3-(parachloro-phenyl)-hexanone-(4=) and its salts. The new substances are intended for application as medicaments. 1 V x According to one feature of the present in.- vention the new alkanones are obtained e.. g..- when para-halogenphenyl-pyridyl alkane carboxylic acid nitriles of the formula Q as,

The starting materials employed in the above *5 Claims. (01. 260-296) 5 processes may be obtained according to customary methods.

According to the method of working the new alkanones are obtained in the form of the free bases or their salts. From the bases salts may be produced, as for example those of the hydro-' halic acids, sulphuric acid, nitric acidjphosphoric acid, acetic acid, propionic acid, oxalic acid, malic acid, citric acid, benzoic acid, salicylic acid, paraaminosalicyclic acid, methane sulphonic "acid, ethane sulphonic acid or toluene sulphonic acid.

The following examples illustrate the invention, the relation between parts by weight and parts by volume being the same asth'at between the kilogram and the liter:

Erample 1 15.1 parts by weight of w-dimethylamino-a- (para-chloro-phenyl) -a-pyridyl- (2) -butyric acid nitrile, dissolved in parts by volume of absolute benzene, are added to a Grignard solution produced from 4.7 parts by weight of magnesium, 100 parts by volume of absolute ether and 26.1 parts by weight of ethyl bromide, the addition being made in portions, and the whole is then heated under reflux for one hour. The reaction mixture is poured into a mixture consisting of 200 parts by weight of ice and 100 parts by volume of concentrated hydrochloric acid and allowed to stand for one hour. The ethereal solution is separated and the acid aqueous solution rendered alkaline to phenolphthalein with caustic soda solution and extracted with ether. The "ether extract is dried over potassium carbonate, the solvent distilled off and the residue distilled in high vacuum. g, The l-dimethylamino-S-(parachloro phenyl) -3 -pyridyl- (2f) -hexanone- (4) of the formula o tLom-om ture has been maintained for 2 hours at C., it Y is treated with water, the benzene solution extracted with dilute mineral acid, the acid extract rendered alkaline, the w-dimethylaminoa- (parach10ro-phenyl)-butyric acid nitrile produced extracted with ether and the ethereal solution dried, the solvent evaporated and the residue distilled in high vacuum. The product distills at 114-116 C. under a pressure of 0.2 mm. Its hydrochloride melts at 165-170 C.

16.1 parts by weight of w-dimethyla'mino-a (para-chloro-phenyl) -butyri c acid nitrile are dissolved in 150 parts by volume of absolute toluene and at a temperature of -60 0.,"312 parts by weight of powdered sodamide added. After the reaction mixture has been left for one hour at this temperature, the reaction temperature is raised to -80" C., and in portions 14.1 parts by weight of 2-bromo-pyridine introduced. Finally the whole is maintained for one hour at C., allowed to cool, treated with water, the toluene solution extracted with dilute hydrochloric acid and the acid extract rendered alkaline with caustic soda solution and extracted with ether. The ethereal solution is dried with potassium carbonate, the solvent distilled ed and the residue distilled under reduced pressure. The dimethylamino a. (para-chloro-phenyl)v.-pyridyl-(2)-butyric acid nitrile of the formula passes over as a viscous oil at 154-164! C. under a pressure of 0.2 mm.

Example 2 into a mixture of 200 parts by weight of ice and parts by volume of concentrated hydrochloric acid, and the whole is allowed to stand for 1 hour with occasional stirring. By the method of working up described in Example 1, there is obtained 1 diethylamino 3 (para chlorophenyl) 3 pyridyl-(2)-hexanone-(4) of the formula R (ll-Q d-om-om C /C2Hs \CH2-CH2-N N CzHS in the form of a yellow oil of boiling point 168 C. under 0.15 mm. pressure.

The to diethylamino-a-(para-chloro-phenyl) c-pyridyl-(2)-butyric acid nitrile used as starting material in this example can be prepared in a manner analogous to that described in Example 1 by using for the reaction, instead of 12.8 parts by weight of ,8-chlorethyl-dimethylamine, 16.3 parts by weight of fl-chlorethyl-diethylamine and then converting the w-diethylamino-a-(parachloro-phenyl) -butyric acid nitrile of boiling point 130-134 C. (under 0.4 mm. pressure) by means of Z-brOmo-pyridine and sodamide into the w diethylamino-a-(para-chloro phenyl)-apyridyl-(2) -butyric acid nitrile of the formula 19.1 parts by Weight of w-(N-methyl-N-cyclo heptylamino) -a (para-chloro-phenyl) -a-pyridyl- (2) butyric acid nitrile, dissolved in 100 parts by volume of absolute benzene, are added in por- (ill tions to a Grignard solution, prepared from 4.8 parts by Weight of magnesium, 27.5 parts by weight of ethyl bromide and 80 parts by volume of absolute ether at a temperature of 40-45" C. and the whole then stirred for one hour at this temperature. By the method of working up described in Example 1, there is obtained the l-(N- methyl-N-cycloheptyl-amino) -3-(para chloro phenyl)-3-pyridy1-(2)-hexanone-(4) of the formula Ha CH2CH2 H2 in the form of a thickly liquid oil with a greenish fluorescence, which boils at 198-207 C. under 0.25 mm. pressure, and which can be converted into the water soluble hydrochloride in the usual manner by treatment with hydrochloric acid as.

The a: (N methyl N-cycloheptyl-amino) -o.- (para-chloro-phenyl) -e-pyridyl- (2) -butyric acid nitrile of boiling point 210-218 C. (under 0.2 mm. pressure) can be prepared e. g. by the method described in Example 1. By starting fromparachloro-benzylcyanide and reacting with ,B-chlorethyl-N-methyl-N-cycloheptyl-amine by means of sodamide, there is obtained w-(N-methyl-N- cycloheptylamino) -u-(para-chloro-phenyl) butyric acid nitrile boiling at 180-185 C. under 0.15 mm. pressure which can be converted with 2- bromo-pyridine and sodamide as. condensing,

agent into the w-(N-methyl-N-cycloheptyl amino) -a(para-chloro-phenyl) ea-IJYYidYl (2) butyric acid nitrile of the formula CHa-CHz-C Hi 5 termediately formed Schiff base, subsequent N- methylation, and conversion of the resultant B'- hydroxyethyl-Nmethyl-N-cycloheptyl-amine by means of thionyl chloride into the ,B-chlorethyl- N-methyl-N-cycloheptyl-amine.

Example 4 10.2 parts by weight of w-(N-methyl-N-cyclopentyl-amino) a. para-chloro-phenyl) -a-pyridyl-(2) -butyric acid nitrile, dissolved in 7 70 parts by volume of absolute'benzene, are addedin portions to a Grignard solution, prepared from 2.7 parts by'weight of magnesium, 50 parts by volume of absolute ether and 12.0 parts by weight of n-propyl bromide at 40-45 C. and the reaction mixture then allowed to stand for one hour at thistemper'ature. By the method of working up described in Example 1, there is obtained 1-(N-methyl-N-cyclopentyl amino) 3 (para-chloro-phenyl) -3-pyridyl- (2) -heptanone (4) of the formula CH3 CH2- H2 in the form of a highly viscous, yellow oil of boiling point 192-19'7 C. (under 0.2 mm. pressure).

The hydrochloride, prepared by dissolving the base in ethyl acetate and adding an equivalent quantity of hydrochloric acid gas, dissolved in ethyl acetate, is a hygroscopic salt which readily dissolves in water.

The w-(N-methyl N cyclopentyl amino) -a.- (para-chloro-phenyl) -a-pyridyl- (2) -butyric acid nitrile used as starting material in this example can also be prepared by the methods described in the preceding examples, starting from parachloro-benzylcyanide, which is reacted with pchlorethyl-N-methyl N cyclopentyl amine by means of sodamide as condensing agent to form the w- (N-methyl-N-cyclopentyl-amino) -a-(parachloro-phenyl) -butyric acid nitrile, which in turn is condensed with sodamide and 2-bromo-pyridine to w- (N-methyl-N-cyclopentyl-amino) -a- (parachloro-phenyl) -a-pyridyl- (2) -butyric acid nitrile of the formula boiling at 185-191 C. under 0.2 mm. pressure.

Example 5 In a manner analogous to that described in the foregoing examples, there may be obtained 1- pyrro1idino-3-(para-chloro-phenyl) 3 pyridyl- (2) -hexanone-(4) of boiling point 165-172 C. (under 0.3 mm. pressure) having the formula CHr-CH:

6 chloride from the product by proceeding in the usual way. The w-pyrrolidino-a- (para-chloro-phenyl) -apyridyl- (2) -butyric acid nitrile can also be prepared in analogy to thd'method of the precedin examples, the w-pyrrolidino a. (para-chlorophenyl) -butyric acid nitrile of boiling point 138- 143 C. (under 0.25 mm. pressure) being obtained as intermediate product.

Example 6 From w-piperidino-a- (para-chloro-phenyl) aapyridyl- (2) -va'1eric acid nitrile boiling at 193-198 C. under 0.25 mm. pressure, there is obtained by reaction with methyl-magnesium-iodide, the 1- piperidlno- 4 -(para-chloro-phenyl) 4 pyridyl- (2)-hexanone-(5) of boiling point 176-182 C. (under 0.25 mm. pressure) and having the formula (mi-0H5 w-Piperidino a (para-chloro-phenyl) -a-pyridyl-(2) -valeric acid nitrile, the starting material used in this example, can be prepared according to the preceding examples from para-chloro-- C CH:

H; CH!

What we claim is:

1. A member of the group consisting of parahalogen-phenyl pyridyl alkanones and their salts, the said alkanones being of the formula wherein R stands for an alkylene radical with two to six carbon atoms, R1 stands for a member of the group consisting of lower alkyl \ower alkyl cycloalkyl lower alkyl piperidino and pyrrolidino radicals, and R2 represents a lower alkyl radical, and Hal is a halogen atom.

wherein R stands for an alkylene radical with two to six carbon atoms, and R2 represents a lower alkyl radical with one to six carbon atoms, and Hal is a halogen atom.

3. An acid salt of a para-halogenphenyl-pyridyl-alkanone of the formula .HaFQ' /COR2 N \CH wherein R stands for an alkylene radical with two to six carbon atoms, and R2 represents a lower alkyl radical with one to six carbon atoms, and Hal is a halogen atom.

4. l-dimethylamino-3- (para-ohloro-phenyl) -3- pyridyl- (2') -hexanone- (4) 8 5. An acid salt of 1-dimethylamino-3-(parachloro-phen'yl) -3 -pyridyl- (2') -hexanone- (4) KARL HOFFMANN. EUGEN TAGMANN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,411,664 Miescher et a1 Nov. 26, 1946 2,542,466 Blicke Feb. 20, 1951 FOREIGN PATENTS Number Country Date 11,197 Great Britain 1906 884,740 France Aug. 25, 1943 589,625 Great Britain June 25, 1947 OTHER REFERENCES Tislow et a1.: Federation Proc., vol. 8, p. 338 (1949).

Bookmuhl et a1.: Liebigs Ann., vol. 561, pp. 52- (1948). 

1. A MEMBER OF THE GROUP CONSISTING OF PARAHALOGEN-PHENYL - PYRIDYL - ALKANONES AND THEIR SALTS, THE SAID ALKANONES BEING OF THE FORMULA 